The present invention relates to novel triazolo[4,3-a]quinazoline-5-ones and/or xe2x88x925-thiones useful for drug preparation for treatment by therapy with a phosphodiesterases 4 inhibitor. These drugs are useful in particular as anti-inflammatories, anti-allergics, bronchodilatators, anti-asthmatics, or TNF xcex1. inhibitors.
The cyclic adenosine 3xe2x80x2, 5xe2x80x2-monophosphate (AMPc) is an second ubiquitous intracellular messenger, acting as an intermediate between a first messenger (hormone, neurotrasmitter, or autacoid) and the cellular functional responses: the first messenger stimulates enzyme responsible of the AMPc synthesis; AMPc intervenes then, relying of the cells implicated, in very numerous functions: metabolic, contractile, or secretory.
The effects of AMPc terminate when it is broken down by cyclic nucleotide phosphodiesterases, intracellular enzymes that catalyze its hydrolysis into inactive adenosine 5xe2x80x2-monophosphate. In mammals we distinguish at least seven large families of cyclic nucleotide phosphodiesterases (PDE) numbered from 1 to 7 according to their structure, their kinetic behavior, their substrate specificity, or their sensitivity towards effectors (Beavo J. A. et al (1990) Trends Pharmacol. Sci. 11, 150-155. Beavo J. A. et al (1994) Molecular Pharmacol. 46, 399-405). PDE4s are specific to AMPc.
Some phosphodiesterase non-specific inhibitors are known as inhibiting several families of enzymes. This is the case for some methylxanthins like theophyllin. These compounds have a weak therapeutic index, in particular because of their action on some classes of PDE present in cells other than target cells. Additionally, some families of PDE may be selectively inhibited by various pharmacological agents : hydrolysis of cyclic nucleotides slowed down and therefore their concentration increase in only cells the type of PDE sensitive to the inhibitor is found. Of interest are the phosphodiesterases 4 (PDE4), which have been identified in numerous tissues including the central nervous system, heart, vascular endothelium, vascular smooth muscle and the one of air passage muscle, myeloid and lymphoid lines. AMPc increase in cells implicated in inflammation inhibits their activation:inhibition of synthesis and mediator release in mastocytes, monocytes, eosinophil and basophil polynuclears, inhibition of chimiotactism and degranulation of eosinophil and neutrophil polynuclears, inhibition of division and differentiation of lymphocytes.
The cytokins, in particular TNF and interleukins, produced by different leukocyte classes such as T lymphocytes and eosinophil polynuclears, play an important role in the triggering of inflammatory manifestations in particular in response to stimulation by an allergen in respiratory tracts.
Further, AMPc decreases air passage smooth muscular fiber tonicity; PDE4 inhibitors bring about bronchorelaxation.
Chronic obstructive pneumopathy (chronic obstructive pulmonary disease or COPD) is a chronic pathology, of slow evolution, characterized by obstruction of respiratory tracts (associated with inflammation of respiratory tracts and elevated neutrophil count). Pulmonary function alteration is largely irreversible (although improvement is possible after treatment by bronchodilatators).
Clinical presentation of chronic obstructive pneumopathy may fluctuate according to attack severity, going from simple non-invalidating chronic bronchitis to very invalidating conditions like chronic respiratory insufficiencies. The main clinical characteristics of patients suffering from chronic obstructive pneumopathy are chronic bronchitis and/or emphysema (associated with respiratory tract inflammation and/or elevated neutrophil count). Over the last years, some selective inhibitors of second-generation phosphodiesterase 4 have been suggested as potentially efficient agents in treatment of chronic obstructive pneumopathy. See, among others, Doherty, Chemical Biology 1999, 3:466-473; Mohammed and al, Anti-inflammatory and Immunodilatory Investigational Drugs 1999 1(1):1-28 ; Schmidt and al, Clinical and Experimental Allergy, 29, supplement 2, 99-109.
Ariflo that is a PDE 4 inhibitor active by oral route, has been suggested for chronic obstructive pneumopathy treatment. See, among others : Nieman and al, Am J Respir Crit Care Med 1998, 157:A413; Underwood and al, Eur Respir J 1998, 12:86s; Compton and al, Am J Respir Crit Care Med 1999, 159:A522. See also the oral presentation by Compton during the meeting of the xe2x80x9cEuropean Respiratory Societyxe2x80x9d which was held in Madrid, on 12th October 1999, as well as the one by Torphy and Underwood during the 4th worldwide congress on inflammation which was held in Paris, from 27th to 30th June 1999. Ariflo is currently under study, in some phase III clinical trials, for chronic obstructive pneumopathy treatment.
However, we should point out that Ariflo has some drawbacks. Indeed some significant adverse events, of the nausea and vomiting type, have been reported after administering of a dose of 20 mg as a single intake. See Murdoch and al, Am J Respir Crit Care Med 1998, 157:A409. Appearance of adverse effects at such low doses will limit the call for Ariflo and prevent use of daily single dosage pharmaceutical, leading therefore to patient discomfort. Osteoporosis is a disease characterized by bone mass decrease and skeleton architecture loss, leading to bone fracture. A large number of women, at the post-menopausal stage, suffer this disease and patient numbers keeps increasing.
Two types of distinct cells exist in bone : osteoblasts, which participate in bone formation; and osteoclasts, which play a role in bone resorption. More particularly, bone mass results from the sum of bone formation by osteoblasts and bone resorption by osteoclasts. Consequently, molecules inhibiting bone resorption induced by osteoclasts are efficient in osteoporosis treatment. Calcitonin, biphosphonates and possibly estrogens are agents fighting against resorption and they are used in the clinical area Molecules stimulating bone formation by osteoblasts also constitute some promising agents in osteoporosis treatment. See also, Yoshihiro et al Jpn. J. Pharmacolog. 1999, 79, 477-483. For several years, extensive research has been performed to obtain and develop powerful PDE4 inhibitors. This has proved to be difficult due to the fact that lots of potential PDE4 inhibitors have some activity on phosphodiesterases in other families.
To date, the lack of selectivity of PDE4 inhibitors represents then an important problem, given the extent of functions regulated by AMPc. There is now a need for powerful and selective PDE4 inhibitors, thus without effect on PDE belonging to other families.
European patent EP 0076199 disclosed compounds with the following general formula: 
in which R and Rxe2x80x2, identical or different, represent H, halogen, alkyl C1-3, alkoxy or nitro; Y represents alkyl cycloalkyl C3-8, alkenyl C2-4, aryl ou aralkyl group, and B represents (CH2)n with n=1, 2, 3 or CH(CH3). The use of these compounds is suggested for treatment of asthma, bronchitis and allergic disorders.
Patent DDR158549 disclosed compounds with the following general formula: 
in which R1 represents H, alkyl or aryl; R2 and R3 represent H, alkyl, halogen, OH, SH, O-alkyl, S-alkyl; R4 represents H, alkyl, halogenoalkyl, OH, SH, O-alkyl, S-alkyl, SO2-alkyl, NH2, SCN, aryl, (CH2)nCOOalkyl and n=0 to 2. The use of these compounds is suggested as am diuretics and antianaphylactics.
Ram and al., in J.Prakt.Chem, 1990, 332(5), 629-39 describe compounds with the following general formula: 
The use of these compounds is suggested for treatment of high blood pressure.
The invention related to triazolo[4,3-a]quinazoline-5-ones and/or xe2x88x925-thiones of formula I or II: 
I and II are position isomers of group R on nitrogens 3 or 4, in which:
A1 is O or S;
X1 and X2, similar or different, represent:
hydrogen, hydroxy, halogen, amino, nitro, mercapto, cyano, carboxy, lower alkyl, lower alkoxy or xe2x80x94S(O)mR8 in which m is 0, 1 or 2 and R8 is a lower alkyl, possibly substituted by one or several halogen atoms,
xe2x80x94COxe2x80x94Q1xe2x80x94Q2xe2x80x94Q3 in which:
xe2x80x94Q1xe2x80x94 is: a simple valence bond, xe2x80x94Oxe2x80x94, 
where p is an integer between 0 to 3,
and Z1 is CH, N, O or S,
xe2x80x94Q2xe2x80x94 is:
a) xe2x80x94(CH2)qxe2x80x94, q being equal to 0, 1, 2, 3, or 4, or
b) xe2x80x94(CH2xe2x80x94CH2xe2x80x94O)rxe2x80x94, r being equal to 2, 3, or 4, and
xe2x80x94Q3 is: xe2x80x94H, xe2x80x94OH, lower alkoxy, xe2x80x94Oxe2x80x94COxe2x80x94X3xe2x80x94NHX3 or 
xe2x80x83in which X3 and X4, similar or different, represent one group lower alkyl, X3 and X4 could be bound to form a cycle, including one or several heteroatoms chosen amongst O, S or N,
xe2x80x94NHxe2x80x94R1 in which R1 represents a lower alkyl group, possibly substituted by one or several groups chosen amongst halogen, hydroxy, cyano, lower alkoxy or xe2x80x94COxe2x80x94Q1xe2x80x94Q2xe2x80x94Q3, or
xe2x80x94NR2R3 in which R2 and R3, similar or different, represent a lower alkyl, possibly substituted by one or several hydroxy, halogen, cyano, lower alkoxy or xe2x80x94COxe2x80x94Q1xe2x80x94Q2xe2x80x94Q3 groups, R2 and R3 being able to be linked to form a cycle, including one or several heteroatoms chosen amongst O, S or N and possibly bridged by a lower alkyl, gem dialkylated or substituted by one or several groups chosen amongst hydroxy, keto, lower alkyl, alkoxy or xe2x80x94COxe2x80x94Q1xe2x80x94Q2xe2x80x94Q3;
R represents:
lower alkyl, lower alcenyl, lower alkynyl, aryl alkynyl, 2, 3 or 4 pyridylalkyl possibly substituted by a lower alkyl, a lower alkoxy, a 
xe2x80x83hydroxy, halogen or amino group,
in which:
n is an integer between 1 and 5,
Ar is an aromatic cycle including 5 or 6 atoms with 0 to 3 heteroatoms chosen among O, S or N.
Y1, Y2 and Y3, similar or different represent:
hydrogen, hydroxy, mercapto, amino, nitro, halogen, xe2x80x94NHR1, xe2x80x94NHR2R3, xe2x80x94(CH2)sxe2x80x94CN, xe2x80x94(CH2)sOxe2x80x94Q1xe2x80x94Q2xe2x80x94Q3 in which s is an integer between 0 to 6;
lower alkyl, lower alkoxy or xe2x80x94S(O)mR8 in which m is 0, 1 or 2 and R8 is a lower alkyl, each one may be possibly substituted by one or several halogen atoms; and
R4 and R5, represent:
lower alkyl when R4 and R5 are similar, aralkyl, cycloalkyl or cycloalkyl alkyl, when R4 and R5 are different,
lower alkyl, R4 and R5 being able to be linked to form a saturated cycle or including one or several double-bonds including one or several heteroatoms chosen among O, S or N and possibly substituted by lower alkyl, hydroxy or lower alkoxy or bridged by a lower alkyl, gem dialkylated or substituted by one or several groups chosen from hydroxy, keto, lower alkyl, lower alkoxy, phenyl alkyl or COxe2x80x94Q1xe2x80x94Q2xe2x80x94Q3, two atoms of a cycle then formed may also be part of another cycle chosen among phenyl or heteroaryl comprising from 4 to 8 atoms with 1 to 4 heteroatoms;
possibly their racemic forms and their isomers, as well as their pharmaceutically acceptable salts.
Compounds of the present invention are useful as inhibitors, particularly as selective inhibitors of phosphodiesterase enzyme, and more particularly the PDE4 enzyme.
The invention relates also to compounds mainly used as synthesis intermediaries of a formula I or II compounds.
A first series of intermediaries includes compounds having the following general formula III: in which: 
X1, X2 and A1 are such as defined previously;
the dotted lines represent optional double-bonds;
R6 is hydrogen; and
R7 is S or hydrazino;
R7 being able to be linked to nitrogen on R6 to form a cycle, particularly a triazole, possibly substituted by a lower thioalkyl, mercapto or halogen group.
A second series of intermediaries includes compounds having the following general formula IV: 
in which X1, X2, A1, R4 and R5 are such as previously defined.
A third series of intermediaries includes compounds having the following general formula V: 
in which X1, X2, A1 and R are such as previously defined and X5 is a halogen group, particularly F, Br or Cl, xe2x80x94OCOX7, xe2x80x94OSO2X7 or xe2x80x94SO2X7 in which X7 is a lower alkyl or an aryl group.
A fourth series of intermediaries include compounds having the following general formula VI 
in which X2, X5, A1 and R are such as previously defined.
A fifth series of intermediaries include compounds having the following general formula VII: 
in which X2, A1, R2 and R3 are such as previously defined, X5 is a halogen group, particularly F, Br or Cl, xe2x80x94OCOX7, xe2x80x94OSO2X7 or xe2x80x94SO2X7 in which X7 is a lower alkyl or an aryl group.
The invention relates also to a process for producing formula I and II compounds. The process is characterized as including the reaction of general formula IV compounds: 
in which X1, X2, A1, R4 and R5 are such as previously defined, with a general formula compound
Rxe2x80x94Xxe2x80x2
in which R is such as previously defined and Xxe2x80x2 is a halogen group, particularly F, Br or Cl, xe2x80x94OCOX7 or xe2x80x94OSO2X7 in which X7 is a lower alkyl or aryl group;
to obtain a mixture of general formula I and II compounds which are then possibly separated.
General formula I compounds can be also prepared by a process characterized in that it includes reacting general formula V compounds: 
in which X1, X2, A1 and R are such as previously defined and X5 is a halogen group, particularly F, Br or Cl, xe2x80x94OCOX7, xe2x80x94OSO2X7 or xe2x80x94SO2X7 in which X7 is a lower alkyl or an aryl group; with a general formula compound:
HNR4R5
in which R4 and R5 are such as previously defined, to obtain a general formula I compound.
In particular manner, when X1 is xe2x80x94NR2R3 and xe2x80x94NR2R3 and xe2x80x94NR4R5 are identical, general formula I compounds adhering to this definition can be obtained by reacting with a general formula VI compound: 
in which X2, X5, A1 and R are such as previously defined, with a general formula compound:
HNR2R3
in which R2 and R3 are such as previously defined, to obtain a general formula I compound: 
Also in particular manner, when X1 is xe2x80x94NR2R3 and xe2x80x94NR2R3 and xe2x80x94NR4R5 are different, general formula I compounds adhering to this definition can be obtained by reacting with a general formula VII compound: 
in which X2, X5, A1, R, R2 and R3 are such as previously defined, with a general formula compound:
HNR4R5
in which R4 and R5 are such as previously defined, to obtain a general formula I compound: 
Also in particular manner, when X1 is H and X2 is OH, general formula I compounds adhering to this definition can be obtained by subjecting a general formula Ia1 compound: in which A1, R, R4 and R5 are such as previously defined and P is a protector group, 
to conditions allowing protector group P elimination to obtain a general formula I compound.
Also in particular manner, when X1 is H and X2 is NH2, formula I compounds adhering to this definition can be obtained by subjecting a general formula Ia2 compound in which A1, R, R4 and R5 are such as previously defined and P1 is protector group, 
to conditions allowing elimination of the protector group P1 to obtain a general formula I compound.
Also in particular manner, when X1 is H and X2 is NHR2 in which R2 is such as previously defined formula I compounds adhering to this definition can be obtained by reacting with a general formula Ib compound 
in which A1, R, R4 and R5 are such as previously defined, with a formula R2X5 compound in which R2 and X5 are such as previously defined, to obtain a general formula I compound.
Moreover, when X1 is H and X2 is NHR2 in which R2 is such as previously defined, formula I compounds adhering to this definition can be also obtained by subjecting a general formula Ib2 compound: 
in which A1, R, R4 and R5 are such as previously defined and P1 is a protector group, to conditions allowing protector group elimination, to obtain a general formula I compound.
Also in particular manner, when X1 is H and X2 is NR2Rx in which R2 is such as previously defined and Rx, represents R2 or R3 as previously defined, formula I compounds adhering to this definition can be obtained by reacting with a general formula Ic compound: in which A1, R, R2, R4 and R5 are such as previously described, 
with a formula RxX5 compound in which Rx and X5 are such as previously defined, to obtain a general formula I compound.
Also in particular manner, when R is 
formula I compounds adhering to this definition can be obtained by dehydration of a general formula Ig compound: 
in which X1, X2, A1, R4 and R5 are such as previously defined, to obtain a general formula I compound.
Also in particular manner, when R is 
formula I compounds adhering to this definition can be obtained by reacting with a general formula If compound: 
in which X1, X2, A1, R4 and R5 are such as previously defined, with ammonia to obtain a general formula I compound.
Also in particular manner, when R is 
formula I compounds adhering to this definition can be obtained by reacting with a general formula If compound with hydroxylamin to obtain a general formula I compound.
Also in particular manner, when R is 
formula I compounds adhering to this definition can be obtained by reacting with a general formula If compound with a formula R11NH2 compound in which R11 has the same significance than R2, to obtain a general formula I compound.
Also in particular manner, when R is 
formula I compounds adhering to this definition can be obtained by reacting with a general formula If compound with a formula HNR12R13 compound in which R12 and R13 have the same significance than R4 and R5 respectively, to obtain general formula I compound.
The invention relates also to a pharmaceutical composition including a formula I or II compound and a pharmacologically acceptable carrier.
The invention relates also to the use of a formula I or II compound for drug preparation in treatment disease or illness relying on therapy by phosphodiesterase inhibition, and more particularly of PDE4.
The invention relates also to a treatment method relying on therapy by phosphodiesterase inhibition, and more particularly of PDE4, said method including administering an effective concentration of a formula I or II compound to a patient.